PROJECT SUMMARY/ABSTRACT Tobacco use rates in the United States (US) have been steadily declining over the past several decades, though the burden resulting from tobacco continues to be staggering. Tobacco use rates are disproportionately high among those with co-occurring substance use disorders and psychiatric conditions compared to the general population. In particular, cannabis co-use among tobacco users is exceedingly common and rates of co-use appear to be increasing among adults in the US, which is consistent with overall increases in cannabis use rates among US adults. Given the current cannabis landscape, further increases in cannabis use are likely and may result in continued increases in the co-use of cannabis and tobacco. Despite high rates of co-use, there is little consensus regarding treatment recommendations for this population and an understanding of the impact of co-use on successful cessation. The literature on the impact of cannabis on tobacco cessation outcomes specifically has been mixed and fraught with limitations, including methodological variation, lack of biochemical verification to confirm cannabis use status and severity, and variations in study samples. Currently, no prospective studies have been conducted to evaluate the impact of cannabis use on tobacco cessation. Further, no studies have collected cannabis use changes during tobacco treatment to assess for reductions, abstinence, or of greater concern, compensatory (i.e., increased) use as a result of tobacco reduction/abstinence. This proposed application is a prospective 12-week tobacco cessation trial using established methods and outcomes typical of tobacco cessation trials, but specifically recruiting co-users of cannabis. Co-users will be oversampled (2:1) and will be compared to tobacco only participants. All participants (ages 18-40; N=172) will receive active tobacco cessation treatment (varenicline, contingency management, and psychosocial counseling) for 12 weeks, while cannabis use will not be specifically addressed. Biochemical verification of tobacco and cannabis use will be collected throughout the 12-week treatment, in addition to self-reports of use through mobile daily dairies. The aims of this proposed study are to; 1) examine the impact of cannabis co-use on tobacco cessation outcomes among co-users compared to tobacco only participants (Aim #1), 2) among cannabis co-users, assess changes in cannabis use during tobacco treatment (Aim #2), and 3) assess for a dose-dependent impact of cannabis co-use severity on tobacco cessation (Exploratory Aim #1). The results from this proposed application have the potential to impact the treatment of tobacco use disorder among those concurrently using cannabis and will contribute to treatment recommendations for providers. As cannabis use rates continue to increase, the presence of co- users in tobacco cessation trials and presenting in clinical care will continue to be common and results from this study will help to guide their treatment and provide them with the best chances of long-term abstinence.